Future drugs may snap supply chain fueling breast cancer

Cancer cells have an insatiable appetite for energy as they multiply more rapidly than normal cells. Greedy cancer cells hijack various cellular functions to find and exploit energy and other resources, including a group of enzymes that help normal cells maintain a balance of energy.

These enzymes, called creatine kinases (CK), allow cells to transport energy produced at the mitochondria to where it is needed throughout the cell. Cancer cells rely on this machinery for shuttling energy to help meet their ravenous fuel demands. Studies of breast cancer cells have highlighted the importance of a type of CK called ubiquitous mitochondrial creatine kinase (uMtCK).

Scientists at Sanford Burnham Prebys and the Mayo Clinic published findings February 3, 2025, in Structure that provide a detailed structure of human uMtCK and show how its structure changes when bound to the energy storage molecules creatine or adenosine triphosphate (ATP). To ascertain the structure of uMtCK, the scientists captured images using cryogenic electron microscopy (cryo-EM). This technology enables investigators to create 3D images of proteins and their ligands by rendering individual atoms. These blueprints may help scientists design new treatments that can stop cancer cells from seizing control of the cells’ energy supply chain to slow or stop tumor growth.

In addition to uncovering the 3D structures of uMtCK and how it interacts with other players involved in energy transport, the research team also tested the only available CK inhibitor called CKi to determine its potential to interrupt abnormal energy transport in breast cancer cells.

The scientists found that CKi successfully reduces breast cancer cell growth. The findings and tools used in this study helped validate that inhibition of the pathway can be effective for the treatment of breast cancer. However, CKi has been shown not to be selective for uMtCK, meaning it is likely to shut down other cellular processes that can lead to high toxicity.

The information provided through cryo-EM methods serves as the foundation for the collaborative team of Mayo Clinic and Sanford Burnham Prebys investigators to design and develop novel small molecules that selectively inhibit uMtCK and thus could provide more effective and less toxic therapeutic agents.

Authors include:

• Merve Demir, PhD, postdoctoral associate in the Conrad Prebys Center for Chemical Genomics (Prebys Center) at Sanford Burnham Prebys, and the lead and corresponding author of the study.
• Eduard Sergienko, PhD, director of Assay Development in the Prebys Center and the senior author of the study. 
• Laura Koepping, Lynn Fujimoto, Andrey Bobkov, PhD, and Jianhua Zhao, PhD, from Sanford Burnham Prebys
• Ya Li and Taro Hitosugi, PhD, from the Mayo Clinic

The study was supported by the National Institutes of Health and National Cancer Institute (R01 CA251910, S10 OD026926 and P30 CA030199), and the Conrad Prebys Foundation.

The study’s DOI is 10.1016/j.str.2025.01.008.